Evidence map›Paper›PMID 42433021›Full record

ArticleHGG advances2026

CRISPR-engineered deletion of POGZ alters transcription factor binding at promoters of genes involved in synaptic signaling.

Mariana Moyses-Oliveira, Yating Liu, Serkan Erdin, Dadi Gao, Riya Bhavsar, Kiana Mohajeri, Kathryn O'Keefe, Philip M Boone, Gabriela Xavier, Calwing Liao and 11 more

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Article in HGG advances, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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4 · The record

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5 · Who and what money

Authors and funding

21 authors.

Mariana Moyses-OliveiraCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA. Electronic address: maricsmoyses@gmail.com.
Yating LiuCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Serkan ErdinCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Dadi GaoCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Riya BhavsarCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Kiana MohajeriCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA, USA.
Kathryn O'KeefeCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Philip M BooneCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA.
Gabriela XavierCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Calwing LiaoCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
Aiqun LiDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Rachita YadavCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Monica SalaniCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Diane LucenteCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Benjamin CurrallCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Celine E F de EschCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Derek J C TaiCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Douglas RuderferDivision of Genetic Medicine, Department of Medicine, Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Medical Center Dr., Nashville, TN 1211, USA; Department of Biomedical Informatics and Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Medical Center Dr., Nashville, TN 1211, USA.
Kristen J BrennandDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Psychiatry, Yale University New Haven, New Haven, CT, USA.
James F GusellaCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA, USA; Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA.
Michael E TalkowskiCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA, USA. Electronic address: mtalkowski@mgh.harvard.edu.

Funding

Broad Institute Mendelian Genomic Research CenterU01HG011755 · NHGRI · BROAD INSTITUTE, INC. · PI Anne O'Donnell-Luria, MICHAEL E TALKOWSKI · 2021 to 2026
$14.6M
High-throughput in vivo and in vitro functional and multi-omics screens of neuropsychiatric and neurodevelopmental disorder risk genesRM1MH132648 · NIMH · YALE UNIVERSITY · PI Kristen Jennifer Brennand, Rong Fan · 2023 to 2026
$5.6M
Scalable tool and comprehensive maps to interpret structural variation across the neuropsychiatric spectrumR01MH115957 · NIMH · BROAD INSTITUTE, INC. · PI TALKOWSKI, MICHAEL E · 2019 to 2025
$5.4M
Functional convergence following disruption of diverse genes associated with neurodevelopmental disordersR01MH123155 · NIMH · YALE UNIVERSITY · PI BRENNAND, KRISTEN JENNIFER, RUDERFER, DOUGLAS · 2021 to 2025
$4.1M
Molecular mechanisms and genetic drivers of reciprocal genomic disordersR01HD096326 · NICHD · MASSACHUSETTS GENERAL HOSPITAL · PI TALKOWSKI, MICHAEL E · 2018 to 2022
$3.5M
Defining the Disorders of Genome OrganizationK08NS117891 · NINDS · MASSACHUSETTS GENERAL HOSPITAL · PI BOONE, PHILIP MICHAEL · 2020 to 2024
$988k
Deep Learning Approaches to Decipher the Impact of Mobile Element Insertion on Alternative Splicing in Neurological DisordersR00NS118109 · NINDS · MASSACHUSETTS GENERAL HOSPITAL · PI GAO, DADI · 2023 to 2025
$696k
NHGRI NIH HHS U01 HG011755NICHD NIH HHS R01 HD096326NIMH NIH HHS R01 MH115957NIMH NIH HHS R01 MH123155NIMH NIH HHS RM1 MH132648NINDS NIH HHS K08 NS117891NINDS NIH HHS R00 NS118109
6 · The paper itself

Abstract

One of the seminal discoveries from genetic studies of autism spectrum disorder and related neurodevelopmental disorders (NDDs) has been that loss-of-function (LoF) mutations in genes that impact transcriptional regulation confer substantial liability to NDDs. Haploinsufficiency of the epigenetic regulator POGZ represents one of the strongest such associations; however, little is known about the mechanisms by which POGZ LoF alters early neuronal development. Here, we created an allelic series of CRISPR-engineered human induced pluripotent stem cell (hiPSC) clones harboring mono- and bi-allelic POGZ deletions. In hiPSC-derived neural stem cells (NSCs) and Neurogenin-2-induced neurons (iNs), POGZ LoF altered the expression of genes associated with synaptic and intracellular signaling and extracellular matrix organization. Our multiomics profiling also showed altered footprinting of critical transcription factors (e.g., activator protein 1 complexes) that were enriched at promoters of differentially expressed genes associated with synaptic function. To further interrogate the shared molecular changes associated with NDDs, we compared our results to deletions of the transcription factor MEF2C and the sodium channel gene SCN2A that we generated in these same isogenic iNs. These analyses revealed strong enrichment of extracellular matrix and intracellular signaling disruption associated with POGZ and MEF2C deletion, whereas POGZ and SCN2A haploinsufficiency exhibited shared transcriptional effects on gene modules enriched for NDD-associated genes with opposing regulatory effects. Notably, we also observed alterations to synaptic firing rate and neurite extension with bi-allelic deletions. These shared molecular consequences suggest key points of convergence that connect gene regulation to neuronal function in the etiology of neurodevelopmental pathologies.

Indexed as

CRISPR-Cas SystemsPromoter Regions, GeneticSynapsesSynaptic TransmissionTranscription FactorsTransposasesBasic Helix-Loop-Helix ProteinsHumansInduced Pluripotent Stem CellsNerve Tissue ProteinsNeural Stem CellsNeuronsProtein BindingSignal TransductionBasic Helix-Loop-Helix ProteinsNerve Tissue ProteinsTranscription FactorsTransposasesautism spectrum disorderchromatin regulatorneurodevelopmentPOGZsynaptic function

Identifiers

PMID42433021
PMCPMC13429924

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.